Tremelimumab, a monoclonal antibody against CTLA-4, in combination with subtotal ablation (trans-catheter arterial chemoembolization [TACE], radiofrequency ablation [RFA] or cryoablation) in patients with hepatocellular carcinoma (HCC) and biliary tract carcinoma (BTC).

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 270-270
Author(s):  
Austin G. Duffy ◽  
Oxana V. Makarova-Rusher ◽  
Drew Pratt ◽  
David E Kleiner ◽  
Suzanne Fioravanti ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Viral Load ◽  
Radiofrequency Ablation ◽  
Immune Cell ◽  
Human Monoclonal Antibody ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Advanced Hcc ◽  
Tumor Biopsies ◽  
Arterial Chemoembolization

270 Background: Tremelimumab is a fully human monoclonal antibody that binds to CTLA-4 expressed on the surface of activated T lymphocytes and results in inhibition of B7-CTLA-4-mediated downregulation of T-cell activation. Transcatheter arterial chemoembolization (TACE), radiofrequency ablation (RFA) and cryoablation (CA) have been shown to induce a peripheral immune response which may enhance the effect of anti-CTLA4 treatment in patients with advanced HCC. Methods: Patients with HCC [Childs Pugh A/B7; BCLC B/C; ECOG 0/1; post-sorafenib (BCLC stage C only)] or refractory BTC were enrolled in a study of Tremelimumab combined with subtotal TACE, RFA or CA performed on week 6. All BTC patients received RFA as the immune-stimulant in combination with tremelimumab. Tumor biopsies were performed at baseline and at time of RF/TACE. Results: 34 pts enrolled (28 HCC, 6 BTC). Characteristics: M:F 26:8; Median age 54(range 42-76); In HCC pts cirrhosis present in 17pts, BCLC Stage B/C: 9/19; Hepatitis B/C/neg: 4/15/9. 13 pts received TACE, 16 underwent RFA (inc 6 BTC pts), 3 CA during week 6 of tremelimumab therapy. 2 pts did not receive an ablative procedure. No DLT encountered. Most common toxicity was pruritus. One patient developed pulmonitis and was taken off study but remained disease-free at 16m. Of N = 17 pts evaluable for response outside of TACE/RFA-treated lesion 4 (23.5%) achieved confirmed partial responses. 8 of 9 pts with quantifiable HCV experienced a marked reduction in viral load. 6-week tumor biopsies showed immune cell infiltration on all evaluable patients. Median PFS for the evaluable HCC population (N = 25) was 5.7m. Conclusions: Tremelimumab in combination with subtotal TACE, RFA or CA in patients with advanced HCC and BTC is safe and feasible. Obtaining tumor biopsies at baseline and at the time of RFA/TACE is safe. Evidence of immune cell infiltration was seen on evaluable patients. Encouraging clinical activity seen with objective confirmed responses, PFS 5.7m and possibly surrogate reductions in HCV viral load. Clinical trial information: NCT01853618.

Tremelimumab: A monoclonal antibody against CTLA-4—In combination with radiofrequency ablation (RFA) in patients with biliary tract carcinoma (BTC).

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 88-88
Author(s):  
Austin G. Duffy ◽  
Drew Pratt ◽  
David E Kleiner ◽  
Donna Mabry ◽  
Suzanne Fioravanti ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Radiofrequency Ablation ◽  
T Cell Activation ◽  
Cell Activation ◽  
Human Monoclonal Antibody ◽  
Immune Monitoring ◽  
Best Response ◽  
Activated T Lymphocytes ◽  
Tumor Biopsies ◽  
Clinical Trial Information

88 Background: Tremelimumab is a fully human monoclonal antibody that binds to CTLA-4 expressed on the surface of activated T lymphocytes and results in inhibition of B7-CTLA-4-mediated downregulation of T-cell activation. Radiofrequency ablation (RFA) has been shown to induce a peripheral immune response which may enhance the effect of anti-CTLA4 treatment. Methods: Patients with refractory BTC were enrolled in a study of monthly Tremelimumab (10mg/kg, 6 doses) combined with RFA (to one lesion) performed on week 6. Tumor biopsies were performed at time of RFA with regular PBMC collection for intensive immunemontoring. Results: 17 pts enrolled. Characteristics: M:F 8:9; Median age 57(range 36-67); BTC subtype - intrahepatic/exrahepatic: 12/5. 13/17 had metastatic disease. All pts were chemorefractory with 12/17 having received at least 2 regimens. While on study, 6 pts had early PD within 6 weeks; 11 were able to undergo RFA. No DLT encountered. Most common toxicity was pruritus. There were no objective responses. Of evaluable pts N = 6 (55%) had stable disease as a best response. Conclusions: Tremelimumab in combination with subtotal RFA in patients with advanced BTC is safe and feasible. No objective responses have so far been seen in this predominantly primary intrahepatic BTC population. Full efficacy and immune monitoring data will be presented. Clinical trial information: NCT01853618.

Hyperglycemia results in decreased immune cell infiltration and increased viral load in the lung in a mouse model of RSV infection

Cytokine ◽  
2021 ◽  
pp. 155539
Author(s):  
Farshad Khodakhah ◽  
Alireza Tahamtan ◽  
Mona Marzban ◽  
Azadeh Shadab ◽  
Masoumeh Tavakoli-Yaraki ◽  
...  
Keyword(s):  
Viral Load ◽  
Mouse Model ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Rsv Infection

scholarly journals 528 Correlation of baseline circulating Vg9Vd2 T cell counts and pharmacodynamic activity of ICT01 in cancer patients: preliminary results from EVICTION and a novel patient enrichment strategy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A558-A558
Author(s):  
Emmanuel Valentin ◽  
Aude de Gassart ◽  
Patrick Brune ◽  
Clément Ghigo ◽  
Sophie Agaugué ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Count ◽  
T Cell Activation ◽  
Immune Cell ◽  
Selection Criterion ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Cell Counts ◽  
Tumor Biopsies

BackgroundICT01, a novel, anti-BTN3A immunotherapeutic mAb for activating g9d2T cells, is currently evaluated in a Phase 1/2a clinical trial in patients with advanced-stage, relapsed/refractory cancer (NCT04243499, EVICTION). ICT01 indirectly activates g9d2 T cells that secrete inflammatory cytokines and migrate into tumors to coordinate antitumor immune responses. Therefore, the baseline number of g9d2 T effector cells constitutes a biomarker of interest and a potential selection criterion for target patients.MethodsFull immunophenotyping (cell counts and activation state) was performed by flow cytometry on fresh blood collected pre- and on-treatment. Serum cytokines were monitored at baseline and post-treatment. Tumor biopsies were harvested at baseline and on Day 28, and multiplex IHC coupled with digital pathology was used to quantify g9d2T cell, CD8 T cell, NK cell, and T reg infiltration and activation stateResultsBaseline circulating g9d2 T cell count was highly variable in solid tumor patients enrolled in the monotherapy arm of EVICTION (median 6918 cell/mL, n=26). Melanoma and colorectal patients displayed respectively the highest (median 42277 cell/mL, n=3) and the lowest (median 3040 cell/mL, n=9) baseline number. During the dose escalation phase, g9d2 T cell activation (CD69+) and migration from the blood was observed 30 min post-ICT01 administration. Serum cytokine levels showed variability within ICT01 dose cohorts. IFNg, TNFa, IL-6 and IL-8 levels post-ICT01 dosing were ICT01 dose dependent and clearly related to baseline number of circulating g9d2 T cells. Activation of peripheral blood NK cells, granulocytes and CD8 T cells was observed post-dosing at ICT01 doses ≥7 mg, which was significantly correlated with baseline g9d2 T cell counts, but not with other immune subsets (Spearman r=0.51, 0.47 and 0.65 for CD69+NK, CD69+CD8 and PD-L1+granulocytes respectively, p<0.05, n=19). Baseline circulating g9d2 T cell count was positively correlated with gdTCR+ T cell density in baseline tumor biopsies (Spearman r=0.76, p=0.0086, n=11). Finally, a trend was observed between baseline g9d2 T cell counts and overall tumor immune cell infiltration and activation post-ICT01 treatment, with 4 patients (out of 13 with available biopsy pairs) with g9d2 T cell counts above the median displaying the highest tumor immune cell infiltration and activation.ConclusionsThese results suggest the utility of measuring baseline g9d2 T cells as part of the patient selection process for ICT01 clinical trials. Patient enrichment based on this biomarker will be tested in EVICTION expansion arms where a minimum baseline threshold of g9d2 T cells counts will be one of the eligibility criteria.Trial RegistrationNCT04243499Ethics ApprovalThe study has obtained Competent Authority and Ethics Committee approvals. Informed consent forms were obtained from all enrolled patients.

Tremelimumab: A monoclonal antibody against CTLA-4—In combination with radiofrequency ablation (RFA) in patients with biliary tract carcinoma (BTC).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 316-316 ◽  
Author(s):  
Austin G. Duffy ◽  
Drew Pratt ◽  
David E Kleiner ◽  
Donna Mabry ◽  
Suzanne Fioravanti ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Radiofrequency Ablation ◽  
T Cell Activation ◽  
Cell Activation ◽  
Human Monoclonal Antibody ◽  
Immune Monitoring ◽  
Best Response ◽  
Activated T Lymphocytes ◽  
Tumor Biopsies ◽  
Clinical Trial Information

316 Background: Tremelimumab is a fully human monoclonal antibody that binds to CTLA-4 expressed on the surface of activated T lymphocytes and results in inhibition of B7-CTLA-4-mediated downregulation of T-cell activation. Radiofrequency ablation (RFA) has been shown to induce a peripheral immune response which may enhance the effect of anti-CTLA4 treatment. Methods: Patients with refractory BTC were enrolled in a study of monthly Tremelimumab (10mg/kg, 6 doses) combined with RFA (to one lesion) performed on week 6. Tumor biopsies were performed at time of RFA with regular PBMC collection for intensive immunemontoring. Results: 17 pts enrolled. Characteristics: M:F 8:9; Median age 57(range 36-67); BTC subtype - intrahepatic/exrahepatic: 12/5. 13/17 had metastatic disease. All pts were chemorefractory with 12/17 having received at least 2 regimens. While on study, 6 pts had early PD within 6 weeks; 11 were able to undergo RFA. No DLT encountered. Most common toxicity was pruritus. There were no objective responses. Of evaluable pts N = 6 (55%) had stable disease as a best response. Conclusions: Tremelimumab in combination with subtotal RFA in patients with advanced BTC is safe and feasible. No objective responses have so far been seen in this predominantly primary intrahepatic BTC population. Full efficacy and immune monitoring data will be presented. Clinical trial information: NCT01853618.

WISP1 modulates immune cell infiltration upon drug-induced liver injury (DILI)

2015 ◽  
Vol 53 (12) ◽  
Author(s):  
AB Widera ◽  
L Pütter ◽  
S Leserer ◽  
G Campos ◽  
K Rochlitz ◽  
...  
Keyword(s):  
Liver Injury ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Drug Induced ◽  
Drug Induced Liver Injury

scholarly journals SFTPA1 is a potential prognostic biomarker correlated with immune cell infiltration and response to immunotherapy in lung adenocarcinoma

2021 ◽  
Author(s):  
Lu Yuan ◽  
Xixi Wu ◽  
Longshan Zhang ◽  
Mi Yang ◽  
Xiaoqing Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Lung Adenocarcinoma ◽  
Expression Profile ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Regulatory Pathways ◽  
Chronic Lung Diseases ◽  
Potential Biomarker

AbstractPulmonary surfactant protein A1 (SFTPA1) is a member of the C-type lectin subfamily that plays a critical role in maintaining lung tissue homeostasis and the innate immune response. SFTPA1 disruption can cause several acute or chronic lung diseases, including lung cancer. However, little research has been performed to associate SFTPA1 with immune cell infiltration and the response to immunotherapy in lung cancer. The findings of our study describe the SFTPA1 expression profile in multiple databases and was validated in BALB/c mice, human tumor tissues, and paired normal tissues using an immunohistochemistry assay. High SFTPA1 mRNA expression was associated with a favorable prognosis through a survival analysis in lung adenocarcinoma (LUAD) samples from TCGA. Further GeneOntology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses showed that SFTPA1 was involved in the toll-like receptor signaling pathway. An immune infiltration analysis clarified that high SFTPA1 expression was associated with an increased number of M1 macrophages, CD8+ T cells, memory activated CD4+ T cells, regulatory T cells, as well as a reduced number of M2 macrophages. Our clinical data suggest that SFTPA1 may serve as a biomarker for predicting a favorable response to immunotherapy for patients with LUAD. Collectively, our study extends the expression profile and potential regulatory pathways of SFTPA1 and may provide a potential biomarker for establishing novel preventive and therapeutic strategies for lung adenocarcinoma.

scholarly journals Enhanced CD4+ and CD8+ T cell infiltrate within convex hull defined pancreatic islet borders as autoimmune diabetes progresses

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alexander J. Dwyer ◽  
Jacob M. Ritz ◽  
Jason S. Mitchell ◽  
Tijana Martinov ◽  
Mohannad Alkhatib ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Convex Hull ◽  
Pancreatic Islets ◽  
Immune Cell ◽  
Nod Mice ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Analytical Strategy ◽  
Islet Mass

AbstractThe notion that T cell insulitis increases as type 1 diabetes (T1D) develops is unsurprising, however, the quantitative analysis of CD4+ and CD8+ T cells within the islet mass is complex and limited with standard approaches. Optical microscopy is an important and widely used method to evaluate immune cell infiltration into pancreatic islets of Langerhans for the study of disease progression or therapeutic efficacy in murine T1D. However, the accuracy of this approach is often limited by subjective and potentially biased qualitative assessment of immune cell subsets. In addition, attempts at quantitative measurements require significant time for manual analysis and often involve sophisticated and expensive imaging software. In this study, we developed and illustrate here a streamlined analytical strategy for the rapid, automated and unbiased investigation of islet area and immune cell infiltration within (insulitis) and around (peri-insulitis) pancreatic islets. To this end, we demonstrate swift and accurate detection of islet borders by modeling cross-sectional islet areas with convex polygons (convex hulls) surrounding islet-associated insulin-producing β cell and glucagon-producing α cell fluorescent signals. To accomplish this, we used a macro produced with the freeware software ImageJ equipped with the Fiji Is Just ImageJ (FIJI) image processing package. Our image analysis procedure allows for direct quantification and statistical determination of islet area and infiltration in a reproducible manner, with location-specific data that more accurately reflect islet areas as insulitis proceeds throughout T1D. Using this approach, we quantified the islet area infiltrated with CD4+ and CD8+ T cells allowing statistical comparison between different age groups of non-obese diabetic (NOD) mice progressing towards T1D. We found significantly more CD4+ and CD8+ T cells infiltrating the convex hull-defined islet mass of 13-week-old non-diabetic and 17-week-old diabetic NOD mice compared to 4-week-old NOD mice. We also determined a significant and measurable loss of islet mass in mice that developed T1D. This approach will be helpful for the location-dependent quantitative calculation of islet mass and cellular infiltration during T1D pathogenesis and can be combined with other markers of inflammation or activation in future studies.

scholarly journals Comprehensive analysis of lncRNA-miRNA-mRNA regulatory networks for microbiota-mediated colorectal cancer associated with immune cell infiltration

Bioengineered ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 3410-3425
Author(s):  
Xiangzhou Tan ◽  
Linfeng Mao ◽  
Changhao Huang ◽  
Weimin Yang ◽  
Jianping Guo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Regulatory Networks ◽  
Immune Cell ◽  
Comprehensive Analysis ◽  
Cell Infiltration ◽  
Immune Cell Infiltration
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